WO2002069933A1

WO2002069933A1 - Tablets quickly disintegrating in oral cavity

Info

Publication number: WO2002069933A1
Application number: PCT/JP2002/002048
Authority: WO
Inventors: Motohiro Ohta; Muneko Kuboyama; Hirokazu Yoshimoto; Yasushi Watanabe; Kiyoshi Morimoto; Makoto Kosugi
Original assignee: Kyowa Hakko Kogyo Co., Ltd.; Taisho Pharmaceutical Co., Ltd.
Priority date: 2001-03-06
Filing date: 2002-03-05
Publication date: 2002-09-12
Also published as: RU2003129506A; JPWO2002069933A1; ES2325484T3; CN1494418A; EP1366759A1; US20040122106A1; KR20030094272A; EP1366759B1; EP1366759A4; JP4365095B2; CA2439873A1; CN1239151C; ATE432692T1; DE60232496D1; AU2002237548B2

Abstract

Tablets quickly disintegrating in the oral cavity without resort of water and sustaining a practically usable tablet hardness which contain: (a) a pharmacologically active ingredient having a solubility in water of at least about 1 mg/ml; (b) crystals or fine particles of D-mannitol having an average particle diameter of primary particles of about 30 µm or more and a specific surface area of about 0.4 m2/g or less; and (c) crospovidone.

Description

Oral quick disintegrating tablets

The present invention relates to tablets that disintegrate rapidly in the oral cavity.

Light

Background technology

Pharmaceutical dosage forms to be administered orally include mainly granules, powders or fine granules, solid preparations such as tablets or capsules, and liquid preparations such as syrups. Here, granules, powders, or fine granules often cause the user to feel discomfort that gets into the gap between the teeth. Solid preparations, such as tablets and capsules, are much easier for users to handle than granules, powders, or fine granules, and are widely used as oral pharmaceuticals. It is difficult to take for weak elderly and children. Since such solid preparations are intended to disintegrate and dissolve in the gastrointestinal tract by oral administration to absorb pharmaceutical components, they generally do not exhibit rapid disintegration or solubility in the oral cavity. On the other hand, syrups are easy to take even for elderly people and children, but have the problem that accurate measurement is difficult to expect.

In response to the current state of such pharmaceutical preparations, with the aging of the population and changes in the living environment, while maintaining the convenience of handling, which is a characteristic of tablets, patients with weak swallowing, such as the elderly and children, can easily There is a demand for the development of an orally disintegrating solid preparation that can be taken and that can be easily taken anywhere, anytime without water. Tablets that disintegrate quickly in the oral cavity are easy to take even for patients with weak swallowing power, and can administer the correct amount of drug unlike liquid preparations such as mouthwashes. In addition, even in general patients other than such patients, when going out where water is not available, etc. Orally disintegrating solid dosage form is a dosage form that can improve drug compliance for all patients.

Here, if the formulation is simply fast-disintegrating, it can be easily obtained by compression-molding the drug prescription component at low pressure, but such a formulation has low formulation strength, and the packaging process, distribution process, In addition, it is quite possible that the product cannot be retained in its shape when it is taken out of the package when the user takes it, and the product is destroyed. Therefore, a rapidly disintegrating preparation in the oral cavity must have both excellent disintegration property in the oral cavity and strength of the preparation that does not cause any problem in handling.

However, tablet solubility and tablet hardness generally have a trade-off relationship with each other. In other words, improving the solubility of the disintegrant and speeding up the dissolution rate leads to deterioration in tablet hardness. However, the tablet hardness is an important factor in the transportation and packaging processes in the manufacturing process as described above, and also in the removal of tablets from the packaging at the time of user taking through the distribution process. If the tablet hardness is insufficient, the tablet cannot maintain its shape in each of the above steps, causing the tablet to lose its shape.

As a technique for preparing a preparation that disintegrates and dissolves rapidly in the oral cavity, a conventional pharmaceutical ingredient is dissolved or suspended in an aqueous solvent, and then filled into a pre-formed bottle of a blister pack, and the solution is freeze-dried. Alternatively, there has been proposed a method of producing by removing the moisture by vacuum drying. Although these solid preparations have rapid solubility, they still have problems such as insufficient mechanical strength or high hygroscopicity in the finished state, making them difficult to handle normally. Furthermore, the method for producing these solid preparations is to heat and melt various compositions, fill them, then solidify them by cooling, or to dry them after filling or press molding them in a wet state. However, there is a problem that it takes a long time to manufacture.

In addition, research on the production of orally disintegrating preparations by wet molding, which is the most commonly used tablet production method, is also underway. Japanese Patent Application Laid-Open No. Hei 9-91 4 8 7 2 6 Discloses a rapidly disintegrating oral preparation containing a drug and a substance which is wettable to form by humidification and maintains the shape by drying after molding, and such substances include saccharides, sugar alcohols, and the like. Water-soluble polymer substances are exemplified. Japanese Patent Application Laid-Open No. 5-271104 discloses a method for tableting a drug, a saccharide, and a mixture containing water to such an extent that the particle surface of the saccharide becomes wet, and drying the mixture. No. 051 describes a method in which a mixture containing a drug, a water-soluble binder, and a water-soluble excipient is tableted at a low pressure, humidified, and dried.

However, the above-mentioned manufacturing method is difficult to use an ordinary tableting machine for tableting a wet mixture, and after tableting, it must be humidified and dried, and the number of manufacturing steps is large. The problem is that it cannot be applied to drugs that are unstable in water.

Japanese Patent Publication No. 6-502191 (U.S. Pat. No. 5,464,632) includes an active substance in the form of coated microcrystals or coated or uncoated fine particles, A rapidly disintegrating multiparticulate tablet comprising an excipient mixture and disintegrating in the mouth in less than 60 seconds is disclosed.

However, in this invention, although it is described that a disintegrant is contained, there is no description about a specific compound. In addition, there is no description of including D-mannitol as an excipient.

Japanese Patent Application Laid-Open No. 11-354550 discloses an improved multiparticulate tablet containing an active ingredient in the form of coated microcrystals and an excipient which decomposes in less than 40 seconds in the mouth ( ^ proved mul t ipart iculate tablet). The tablet may comprise, as excipients, at least one disintegrant, for example crospovidone, and a polyol, for example mannitol, in the form of a directly compressible product with an average particle size of 100-500 m or It is contained in the form of a powder having an average particle diameter of less than 100.

However, in this invention, the specific surface area of mannitol is not described at all. On the other hand, D-mannitol is excellent in safety and incorporation with bioactive substances, and because it has no hygroscopicity and hardly retains water, it contains bioactive substances that are particularly sensitive to water. It is a high-value drug for the formulation of tablets or capsules. On the other hand, D-mannitol has poor bondability during compression molding and has a large friction with the metal wall surface. Therefore, if D-mannitol is included as an excipient, dies, friction (friction) and capping will occur during compression molding. It causes capping, does not provide sufficient hardness to tablets, and causes wear on the mortar wall and punch side of the tablet machine (tabletting machine), sometimes even making it difficult to operate the tablet machine. There's a problem. Therefore, the use of D-mannitol as an excipient is currently limited to extremely limited dosage forms such as chewable tablets.

Here, D-mannitol is a crystalline powder having a polymorphism classified into a; type // 3 type and (type 5 according to the X-ray diffraction pattern [Walter-Levy, L., Acad. 276 Series C, 1779, (1968)] In order to improve the moldability of crystalline powder, that is, to improve the bondability during compression molding, the number of bonding points is generally determined by finely pulverizing the crystals. It is known that the moldability (bonding property during compression molding) is improved by this, but in the case of D-mannitol, simply pulverizing reduces friction with the metal wall surface during compression molding. In addition to contributing, there are problems with handling, such as dusting and poor flowability.

Therefore, conventionally, when D-mannitol is used as an excipient of a compression-molded product, it is rarely used alone, and it is blended with other excipients having good moldability, for example, saccharides, and a binder, a filler, and the like. It is used in combination with other additives such as first.

As a method for improving the moldability of D-mannitol, Japanese Patent Application Laid-Open No. Sho 61-85330 discloses a method for producing a direct-punching excipient characterized by spray-drying D-mannitol. Japanese Patent Application Laid-Open No. 10-36291 discloses a solid composition containing D-mannitol having a specific surface area of about lm ² Zg or more as an excipient having excellent compression moldability. Is disclosed. However, the method for producing D-mannitol used in the invention is complicated and the production cost is high. In addition, during the production of tablets, since the fluidity of the granular material is not sufficient and the mixing with the active ingredient is not sufficient, there is a concern that the uniformity of the tablet weight and content may be reduced.

WO977472728 discloses a tablet containing a sugar alcohol containing D-mannitol having an average particle size of 30 m or less. However, there is room for further improvement in order to reduce the oral disintegration time of the preparation, especially when a water-soluble drug is used as the pharmacologically active ingredient. Disclosure of the invention

An object of the present invention is to rapidly disintegrate in the oral cavity with a practical tablet hardness that disintegrates quickly without water in the oral cavity, and does not cause problems such as shape loss in the manufacturing and distribution processes and in the handling by hospitals and patients. To provide tablets.

The present inventors have disclosed that a pharmacologically active ingredient which can be dissolved in water, preferably has a solubility in water of at least 0.1 mg / ml, more preferably at least lmg / ml in water, is contained as a main ingredient. In order to achieve the above object, a rapidly disintegrating intraorally disintegrating tablet is first examined by trial and error with respect to excipients. As a result, the average primary particle diameter is about 30 m or more and the specific surface area is about 0.4. It is an unexpected finding that the inclusion of D-mannitol crystals or fine particles having a particle size of about m ² ng or less makes it possible to obtain a rapidly disintegrating tablet in the oral cavity having excellent disintegration properties and practical tablet hardness. Was obtained. Furthermore, the present inventors have conducted trial and error studies on disintegrants, and found that it is preferable to use clospovidone, and that if other disintegrants are used, disintegration time in the oral cavity will be prolonged. .

The present inventors have also studied a method for producing such an orally rapidly disintegrating tablet. As a result, the pharmacologically active ingredient, D-mannitol crystals or fine particles containing crospovidone were added. Add the aqueous medium, knead and granulate, If necessary, other additives are added to the granules obtained by drying to prepare a compression-molded material, which is then compression-molded to obtain a tablet hardness (approximately 2 ON or more) at which there is no practical problem. It was found that a rapidly disintegrating tablet in the oral cavity that rapidly disintegrated in the oral cavity could be obtained within about 30 seconds. In particular, according to a method of compression-molding a lubricant-free compression-molded material using a compression-molding machine in which a lubricant has been applied to the surface of a punch and a die wall in advance (referred to as an external lubricating tableting method). We have also surprisingly found that the oral disintegration time can be reduced (within about 20 seconds).

The present inventors have further studied and completed the present invention.

That is, the present invention

(1) pharmacologically active ingredient solubility of more than 0. 5MgZml in water, the average particle diameter of primary particles is is and a specific surface area above 30 m 0. 4m ² Zg hereinafter D- Man'ni Bok Lumpur crystals or fine particles And a rapidly disintegrating tablet in the oral cavity containing crospovidone and

(2) Midodrine or a pharmacologically acceptable salt thereof, containing D-mannitol crystals or fine particles with an average primary particle diameter of 30 m or more and a specific surface area of 0.4 m ² Zg or less, and crospovidone Orally rapidly disintegrating tablets,

(3) The tablet according to any of (1) or (2), further comprising a lubricant,

(4) The tablet according to (3), wherein the lubricant is contained only on the surface of the tablet,

(5) wherein the lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, sodium stearyl fumarate, sucrose fatty acid ester and talc (3) Or a tablet according to any of (4),

(6) Any of (1) to (5) above, further containing at least one selected from the group consisting of a flavoring agent, a sweetening agent, a flavor and a coloring agent, a stabilizer, a superplasticizer, and a solubilizing agent. Tablets described in crabs,

(7) The above-mentioned (1), wherein the compounding ratio of the pharmacologically active ingredient in the tablet is 0.01 to 50% by weight. Tablet according to any one of to (6),

(8) The tablet according to any one of (1) to (7), wherein the content of D-mannitol in the tablet is 20 to 99% by weight.

(9) The tablet according to any one of (1) to (8) above, wherein the compounding ratio of crospovidone in the tablet is 0.5 to 30% by weight.

(10) The tablet according to any one of (1) to (9), wherein the tablet hardness is 2 ON or more.

(11) The tablet according to any one of (1) to (10), wherein the disintegration time in the oral cavity is 30 seconds or less.

(12) The tablet according to any one of the above (1) to (11), wherein the pharmacologically active ingredient is midodrine hydrochloride.

(13) Pharmacologically active ingredient with a solubility in water of 0.5 mg Zml or more, D-mannitol crystals or fine particles and cloth having an average primary particle diameter of 30 or more and a specific surface area of 0.4 m ² Zg or less. An aqueous medium is added to the powdered granules containing povidone, the mixture is kneaded, and then granulated, and then, if desired, other additives are added to the granules obtained by drying to prepare a compression molding material. A method for producing a rapidly disintegrating tablet in the oral cavity, characterized by being molded;

(14) Midodrine or a pharmacologically acceptable salt thereof, D-mannitol crystals or fine particles having an average primary particle diameter of 30 im or more and a specific surface area of 0.4 m ² / g or less, and crospovidone. An aqueous medium is added to the powder and granules containing the mixture, and the mixture is kneaded, and then granulated, and then, if necessary, other additives are added to the granules obtained by drying to prepare a compression molding material. A method for producing an orally rapidly disintegrating tablet,

(15) The above-mentioned (13) or (), wherein the other additive contains at least one selected from the group consisting of a flavoring agent, a sweetener, a flavor and a coloring agent, a superplasticizer, a stabilizer, and a solubilizing agent. 14) The method for producing a tablet according to any one of (16) The tablet production method according to any one of (13.) to (15) above, wherein the powder further contains a lubricant,

(17) The compression molding according to any one of the above (13) to (16), wherein the compression molding is performed using a compression molding machine in which a lubricant is previously applied to the surface of the punch and the wall of the die. Tablet manufacturing method,

(18) The above-mentioned (16) or wherein the lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, sodium stearyl fumarate, sucrose fatty acid ester and talc. (17) The method for producing a tablet according to any one of the above,

(19) The method for producing a tablet according to any one of the above (13) to (18), wherein the compounding ratio of the pharmacologically active ingredient in the tablet is 0.01 to 50% by weight.

(20) The method for producing a tablet according to any one of the above (13) to (19), wherein the content of D-mannitol in the tablet is 20 to 99% by weight,

(21) The method for producing a tablet according to any one of the above (13) to (20), wherein the compounding ratio of crospovidone in the tablet is 0.5 to 30% by weight,

(22) The tablet production method according to any one of (13) to (21), wherein the tablet hardness of the obtained tablet is 2 ON or more,

(23) The tablet production method according to any one of (13) to (22), wherein the obtained tablet has a disintegration time in the oral cavity of 30 seconds or less,

(24) The method for producing a tablet according to any one of the above (13) to (23), wherein the aqueous medium is pure water,

(25) The method for producing a tablet according to any one of the above (13) to (24), wherein the pharmacologically active ingredient is midodrine hydrochloride, and

(26) a pharmacologically active ingredient solubility is more than lmg / ml in water, the average particle child size of the primary particles is that and a specific surface area 30 im or 0. 4m ² Zg hereinafter D_ mannitol Le crystals or fine particles and Orally rapidly disintegrating tablets containing crospovidone, About.

Here, in the above (1) and (13), the pharmacologically active ingredient is preferably a pharmacologically active ingredient having a solubility in water of 1 mg / m 1 or more. BEST MODE FOR CARRYING OUT THE INVENTION

The pharmacologically active ingredient in the orally rapidly disintegrating tablet according to the present invention exhibits physiological activity such as pharmacological activity, and is not particularly limited as long as it is intended for oral administration, but is about 0.5 mg / m 1 or more. A pharmacologically active ingredient having a solubility in water of preferably about 1 mg Zm 1 or more is particularly suitable. Here, the solubility of the pharmacologically active ingredient is determined by the method described in Section 23 of the Japanese Pharmacopoeia 13 General Rules.Specifically, the powder is placed in water, and strongly intensified every 5 minutes at 20 ± 5 ° C. It can be measured by measuring the degree of dissolution within 30 minutes when shaking for seconds.

Specific pharmacologically active ingredients include, for example, antipyretic analgesics and anti-inflammatory drugs, psychotropic drugs, anti-insecure drugs, antidepressants, central nervous system drugs, gastrointestinal drugs, anti-ulcer drugs, antacids, sleep sedatives, brain Metabolic improver, antitussive expectorant, antiallergic, bronchodilator, inotropic, antiarrhythmic, antihistamine, diuretic, antihypertensive, vasoconstrictor, bile, antihyperlipidemic, One or more components selected from coronary vasodilators, peripheral vasodilators, antibiotics, drugs for the treatment of arugahima, and drugs for the treatment of gout.

Examples of the above-mentioned "pharmacologically active ingredient having a solubility in water of about 0.5 mg Zml or more" include, for example, antipyretic analgesic and anti-inflammatory drugs such as acetaminophen or diclofenac sodium; sleep sedatives such as flurazepam hydrochloride. Drugs: Antiepileptic drugs, such as sodium nitrite; antiparkinson drugs, such as amatadine hydrochloride; Psychotropic agents, such as imiplanate hydrochloride or clocabramine hydrochloride; Antiarrhythmic drugs such as sprenol or mexiletine hydrochloride; antihypertensive drugs such as captopril or hydralazine hydrochloride; midodrine hydrochloride or methedimidine methylsulfate Vasodilators such as dilazep hydrochloride or diltiazem hydrochloride; analgesics such as pentoxin verine citrate; expectorants such as ambroxol hydrochloride or L-methyl cysteine hydrochloride; hydrochloric acid Bronchodilators such as clenbuterol or propoterol hydrochloride; or peptic ulcers such as cetraxate hydrochloride, pirenzepine hydrochloride or famotidine. For example, the solubility of midodrine hydrochloride, captopril, amproxol hydrochloride, peramide hydrochloride and famotidine in water is about 10 mg Om Zm 1, about 6 O mgm 1, about 20 mg / m and about 1 mg, respectively. / m 1 and about 0.7 mg / m 1.

The pharmacologically active ingredient in the orally rapidly disintegrating tablet according to the present invention may be a pharmacologically acceptable salt of a compound having a physiological activity or the like. Pharmaceutically acceptable salts include, for example, inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.), organic acids (eg, carbonic acid, bicarbonic acid, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.), Inorganic bases (eg, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or magnesium, etc.) and organic base compounds (eg, organic amines such as triethylamine, basic amino acids such as arginine) and Salts.

Therefore, for example, when the pharmacologically active ingredient in the orally rapidly disintegrating tablet according to the present invention is midodrine, midodrine may be contained in the form of a pharmacologically acceptable salt. For example, there is a case where midodrine hydrochloride is contained.

The primary particles of D-mannitol in the orally rapidly disintegrating tablet according to the present invention have a mean particle diameter of about 30 m or more and a specific surface area of about 0.4 m ² / g or less. The feature is that it is fine particles. Here, the primary particles do not refer to aggregates of particles such as granules, but refer to individual particles constituting the aggregates. Preferred embodiments of the crystals or fine particles have an average particle diameter of preferably about 30 to 1000 m, more preferably about 35 to 300 m, particularly preferably about 40 to 100 m, and preferably about 0 to 100 m. ^{^{. 4~4X 10- 2 () m 2}} / g , more preferably about from about 0. 3~2X 10_ ⁶ m ² Zg about, particularly preferably about 0. 3~0. 02m ² Zg about specific surface area Examples include crystals or fine particles.

Here, the average particle diameter means a 50% particle diameter, and represents a particle diameter at 50% from a cumulative percentage graph. Examples of the measuring method include a laser-diffraction type particle size distribution measuring method, and a specific example is a method using a laser diffraction Z-scattering type particle size distribution measuring device LA-910 (manufactured by Horiba, Ltd.). The specific surface area can be measured by using the BET (Bnmauer-E secret and teller's) method, and specifically, for example, by using a SA-9603 type measuring instrument manufactured by Horiba, Ltd.

The D-mannitol used in the present invention may have any of the crystal forms of a rhombus, a / 3 type or a <5 type. In addition, a cast, a / 3 or a δ-type D-manni! ^ Crystal is an X reported by Walter-Levy, L. [Acad. Sci. Parist. 276 Series C, 1779, (1968)]. It is defined according to the classification of polymorphism of D-mannitol by the line analysis pattern. The D-mannitol may be obtained by a method known per se, such as a liquid extraction method from seaweed, an ammonia electrolytic reduction method of a sucrose solution, and a catalytic reduction method of a sucrose solution.

The method for producing the D-mannitol crystals or fine particles in the orally rapidly disintegrating tablet according to the present invention is not limited as long as it has the above-mentioned features. Specifically, for example, a method of pulverizing D-mannitol particles into a desired size using a known pulverizer such as a jet mill, a hammer mill, a pole mill, a vibrating pole mill, or a bin mill can be used. Alternatively, D-mannitol is dissolved in an appropriate solvent, preferably water (this may be heated to about 60 to 80 ° C.), and preferably As a solution having a concentration of about 10 to 40% by weight, a method of obtaining desired crystals or fine particles by spray drying using a spray dryer known per se can also be mentioned. The spray drying conditions are not particularly limited, but it is preferable that the exhaust heat temperature be about 120 to 140 ° C.

In a preferred embodiment of the method for producing D-mannitol crystals or fine particles used in the present invention, a treatment such as a spray-drying treatment is carried out to obtain a crystal or powder having a specific surface area not increased. There is a method of obtaining crystals or fine particles of D-mannitol having a surface area of about 0. An ^ Zg or less. Further, if the average particle diameter of the obtained crystals or fine particles is about 30 m or more, they can be pulverized using a pulverizer such as a hammer mill or a jet mill, if desired. In other words, by adjusting conditions such as the screen diameter in the case of a hammer mill and the air flow rate or the powder supply speed in the case of a jet mill, the particle size can be adjusted to any desired value (however, the average particle size of the primary particles is about 30 m or more. ) Crystals or fine particles can be obtained.

The crospovidone contained in the orally rapidly disintegrating tablet according to the present invention may be any cross-linked polymer of 1-vinyl-2,1-pyrrolidone, and usually a crospovidone having a molecular weight of 1,000, 0000 or more is used. . The crospovidone is known as a disintegrant and can be produced by a method known per se.

Commercial products such as CL (manufactured by BASF Japan) and polyplasdone XL (manufactured by ISP Japan) may be used.

In the orally rapidly disintegrating tablet according to the present invention, the blending ratio of the above pharmacologically active ingredient (the blending weight ratio of the pharmacologically active ingredient to the total weight of the tablet) is not particularly limited, but is preferably about 0.01 to 50% by weight. It is more preferably about 0.01 to 30% by weight. In the orally rapidly disintegrating tablet according to the present invention, the blending ratio of D-mannitol (the blending ratio of D-mannitol to the total weight of the tablet) is preferably about 20 to 9.9% by weight. In the orally rapidly disintegrating tablet according to the present invention, the blending ratio of crospovidone (the blending weight ratio of crospovidone to the total weight of the disintegrant) is not particularly limited, but is preferably about 0.5 to 30 wt%. It is more preferably about 0.5 to 20% by weight, particularly preferably about 1 to 10% by weight.

The blending ratio (blending ratio) of the above-mentioned pharmacologically active ingredient, crystals or fine particles of D-mannitol and crospovidone in the orally rapidly disintegrating tablet according to the present invention is determined by the solubility, particle size or wettability of the pharmacologically active ingredient in water. It can be appropriately selected depending on the physical properties of the material.

The orally rapidly disintegrating tablet of the present invention preferably contains a lubricant. The lubricant is not particularly limited, but for example, magnesium stearate, calcium stearate, stearyl alcohol, stearic acid, sodium stearyl fumarate, talc or sucrose fatty acid ester is preferably used.

The weight ratio of the lubricant to the orally rapidly disintegrating tablet of the present invention is preferably about 0.001 to 2% by weight, more preferably about 0.01 to 1% by weight, and more preferably about 0.01% by weight. Particularly preferred is about 5 to 0.5% by weight.

Although the lubricant may be contained in the orally rapidly disintegrating tablet of the present invention, it is preferable that the lubricant is contained only on the surface of the tablet by the external lubricating method described below. preferable.

The orally rapidly disintegrating tablet of the present invention may be, if desired, one or two selected from the group consisting of a flavor, a coloring agent, a flavoring agent, a sweetening agent, a stabilizing agent, an antioxidant, a fluidizing agent, and a solubilizing agent. One or more additive components may be included. The additive weight ratio of the additive to the total weight of the tablet is preferably about 5% by weight or less, more preferably about 1% by weight or less, and particularly preferably about 0.5% by weight or less.

Examples of the flavor include L-menthol, lemon, orange, strawberry, mint and the like.

Examples of colorants include yellow iron sesquioxide, red iron sesquioxide, edible yellow No. 5, Food colors such as Food Blue No. 2 and food lake colors.

Examples of the flavoring agent and sweetening agent include aspartame, saccharin sodium, stevia, and dalicyrrhiztin potassium.

Examples of the fluidizing agent include light caustic anhydride, calcium silicate, and synthetic aluminum gaterate.

Examples of the stabilizer include benzoic acid, sodium benzoate, citric acid and the like.

Antioxidants include ascorbic acid, tocopherol and the like.

As a solubilizing agent, a surfactant is typically exemplified, and more specifically, for example, polysorbate 80, sodium lauryl sulfate, macrogol 400 and the like are exemplified.

The additive to be added to the orally rapidly disintegrating tablet of the present invention is not particularly limited, but a tablet which does not contain a saccharide and a binder other than D-mannitol, which exhibits high viscosity when touched with water, is used in the present invention. Particularly preferred. As described above, by not containing the following other saccharides and binders, the disintegration property in the oral cavity of the obtained rapidly disintegrating tablet in the oral cavity tends to be improved.

Here, examples of the saccharides other than D-mannitol include saccharides such as sucrose, glucose, maltose and fructose, and sugar alcohols such as sorbitol and maltitol. Other binders other than D-mannitol include, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), polyvinyl vinylidone (PVP), pullulan, polyvinyl alcohol (PVA) ) Or gelatin.

Such (a) a pharmacologically active ingredient as a main drug having a solubility in water of about 0.5 mg / ml or more, preferably about lmgZml or more, and (b) an average particle size of about 30 m or more and a specific D-manni whose surface area is less than about 0.4m ² Zg The intraoral quick disintegrating tablet according to the present invention, which contains toll, (c) crospovidone and (d) if desired a lubricant and other additives, has a practical hardness and is free of water in the oral cavity. However, it is characteristic that it collapses quickly.

Here, “practical tablet hardness” cannot be said unconditionally because it differs depending on the tablet component and tablet shape, but a hardness of about 2 ON or more, preferably about 3 ON or more is suitable. The tablet hardness can be easily measured using a tablet hardness meter known per se, for example, Model TH-303 manufactured by Toyama Chemical Co., Ltd.

Also, "rapid disintegration" means disintegration by saliva in a time that is practically acceptable without taking water in the oral cavity. Although there is an individual difference with the disintegration time at which there is no practical problem, the disintegration time is preferably within about 30 seconds. Here, the disintegration time is obtained by measuring the time until the orally disintegrating tablet completely disintegrates with the saliva in the oral cavity of healthy adult males and females.

The quick-disintegrating buccal tablet according to the present invention is not limited to taking without water, and it has a merit that even a patient with little saliva can easily take it with water. It can be said that tablets are easy to do. That is, the method for taking the orally rapidly disintegrating tablet according to the present invention includes, for example, (a) a method of dissolving or disintegrating with or without a small amount of water or saliva in the oral cavity without swallowing as it is contained in the mouth. (B) a method in which the tablet is swallowed with water and taken, or (c) a method in which the tablet is dissolved or disintegrated with water and then taken.

Since the orally rapidly disintegrating tablet of the present invention can be taken without water as described above, (a) when it is necessary to take the tablet without water, (b) it is difficult to swallow the tablet It is particularly advantageous when taken by patients, or (c) when taken by elderly or children who may be clogged with regular tablets. Preferred examples of (a) include antipyretics, analgesics, antiphlogistics, anxiolytics, antitussive expectorants, analgesics, or preventive / therapeutic agents for motion sickness. Examples of case (b) include diseases such as hypertension, hyperlipidemia, diabetes, bronchial asthma, and cerebrovascular disease. Prophylactic and therapeutic drugs.

The orally rapidly disintegrating tablet of the present invention is produced by a conventional method in the pharmaceutical field such as a direct tableting method or an indirect tableting method. For example, there is a method in which the above-mentioned pharmacologically active ingredient, D-mannitol, crospovidone and, if desired, a lubricant and other additives are mixed, followed by compression molding.

The “mixing” is performed using a device such as a vertical granulator VG10 (manufactured by Parec), a universal kneader, a fluidized bed granulator, a V-type mixer, a tumbler mixer, or the like. “Compression molding” is performed using a tableting machine known per se, such as a single-shot tableting machine or a rotary tableting machine.

In a preferred embodiment of the method for producing an orally rapidly disintegrating tablet according to the present invention, a tablet obtained by adding an aqueous medium to a granule containing the pharmacologically active ingredient, crystals or fine particles of D-mannitol, and crospovidone is added. A method may be used in which, if desired, an additive other than the above-mentioned constituents of the granular material is added to the granules obtained by granulation and then drying to prepare a compression molding material, which is then compression molded.

In the above-mentioned production method, examples of the aqueous medium include purified water, methanol, ethanol, acetone and a mixture thereof, and the mixing ratio thereof can be appropriately selected. Among them, purified water is preferably used. The amount of the aqueous solvent added to the powder is preferably about 5 to 30% by weight.

The method for granulating the above-mentioned pharmacologically active ingredient, D-mannitol and crospovidone is not particularly limited. However, for all or some of the components, fluidized bed granulation, tumbling fluidized bed, and stirring Granules (preferably, using NSK-250 high-speed stirring granulator manufactured by Okada Seie or PVG VG-250 high-speed stirring granulator), extrusion granulation (preferably, Fujipadal It is preferable to use a granulation method such as wet granulation (using DGL-1 type), but it is also possible to granulate by dry granulation. The particle size and specific surface area of these granules can be arbitrarily set without any particular limitation as long as they have fluidity that does not interfere with tableting. When the orally rapidly disintegrating tablet according to the present invention contains a lubricant, a lubricant may be further added to and mixed with the above-mentioned powdery granules comprising the pharmacologically active ingredient, D-mannitol and crospovidone. Further, other additives (for example, fragrances, stabilizers, etc.) described above other than the lubricant may be added to the powder and mixed, but preferably, as described below, It is preferable to mix the additive to the granulated product obtained by the above.

Next, the above-mentioned granulated product is dried to obtain granules. The drying method is not particularly limited, but a drying machine known per se, for example, a ventilation box dryer (preferably, a Japanese dryer TE-98 type) is used, and is dried at about 40 to 80 ° C. for about 3 hours. Dry for about 0 to 90 minutes, or use a fluid bed dryer (preferably FLO-5, manufactured by Freund Corporation) at a temperature of about 70 to 90 for about 5 to 3 minutes. A method of drying for about 0 minutes is preferable.

The granulation and drying may be performed at once using the above-described fluidized-bed granulator / dryer (preferably, FLO-2 type manufactured by Freund Corporation).

Next, if necessary, the above-mentioned additives other than lubricants such as fragrances and stabilizers are added to the granules to prepare a compression molding material. Then, the orally rapidly disintegrating tablet according to the present invention is obtained by compression molding the compression molded material. The compression molding can be carried out using a known tableting machine, preferably a single-shot tableting machine, a rotary tableting machine, a hydraulic press, or the like having excellent productivity. The pressure during compression molding is about 3 to 30 kN, preferably about 5 to 20 kN.

As another preferred embodiment of the method for producing the orally rapidly disintegrating tablet according to the present invention, the above-mentioned pharmacologically active ingredient, D-mannitol, crospovidone, if desired, a lubricant and other additives described above are known per se. And a tablet obtained by mixing directly with a mixer such as a V-type mixer or a tumbler mixer.

In the production of the orally rapidly disintegrating tablet according to the present invention, as described above, The lubricant may be contained inside the tablet together with the ingredients, but the lubricant is applied to the surface of the punch and die wall of the compression molding machine in advance without mixing the lubricant with other ingredients. Is preferably manufactured by a compression molding method (external lubricating tableting method). This has the advantage that the tablet hardness can be increased or the disintegration time can be shortened. The method of applying the lubricant to the punch and die is not particularly limited. The weight and shape of the orally rapidly disintegrating tablet according to the present invention are not particularly limited. For example, the form of the preparation may be a circular shape or various different shapes having a surface shape such as a regular R surface, a sugar coating R surface, a sumikaku plane, a sumimaru plane, a two-step R surface, and the like. Further, the tablet may be used as a divided tablet having a score line. Further, it may be a multilayer tablet having two or more layers.

In particular, the orally rapidly disintegrating tablet according to the present invention is preferably a small tablet, and the hardness and the orally disintegrating time can be controlled by the weight and Z or shape of the tablet. As the tablet of the present invention, for example, a tablet having a weight of about 80 to 25 O mg and a tablet diameter of about 6 to 9 mm is suitable.

The orally rapidly disintegrating tablet of the present invention is orally administered not only to humans but also to mammals other than humans (eg, mice, rats, rabbits, cats, dogs, rabbits, dogs, monkeys, etc.). Can be safely administered. The dose of the orally rapidly disintegrating tablet of the present invention varies depending on, for example, the drug component, the administration subject, the type of the disease, and the like, but may be appropriately selected from the range where the dose as the drug component is an effective amount. The orally rapidly disintegrating tablet of the present invention may be administered once or more than once a day, preferably about 2 to 4 times. Example

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but these are not intended to limit the present invention. In addition, the solubility of the pharmacologically active ingredient in water was measured by the method described in Section 23 of the Japanese Pharmacopoeia 13 General Rules. D-manni! The average particle size of the primary particles (hereinafter simply referred to as the “average particle size”) is the laser diffraction Z Represents the 50% particle size as measured using a scattering type particle size distribution analyzer LA-910 (manufactured by Horiba, Ltd.). The D-mannitol specific surface area was measured using a SA-9603 type measuring instrument (manufactured by Horiba, Ltd.) according to the BET (Brunauer-Emmett and Teller's) method.

(Example 1)

Midodrine hydrochloride (solubility in water of about 10 OmgZml) 20 g, D-mannitol (Kyowa Hakko No Nikka Kasei Co., Ltd., average particle size 6Οπι, specific surface area 0.1 lmVg) 1 120 g, crospovidone (I 60 g of SPILL, “Polyplasdone XL-10”) was charged into a high-speed agitation granulator (NSK-250, manufactured by Okada Seie), 20 Og of purified water was added, and the mixture was kneaded for 5 minutes. 8 After preparing granules using an extrusion granulator equipped with a πιπιφ screen (manufactured by Nipadadal, Inc., DGL-1 type), use a ventilation box type dryer (Japan dryer 機 -98 type), Dried for 60 minutes. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Φ 7. Attach a punch with an Omm corner plane and use a rotary tableting machine equipped with a device to apply calcium stearate to the surface of the punch and the wall of the die before filling the granules into the die of the tableting machine. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 120 mg and a tablet thickness of 2.6 mm. The tableting pressure was about 7.5 kN. About 0.1% by weight of calcium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Example 2)

Midodrine hydrochloride (solubility in water: about 100 mg Zm 1) 20 g, D-manni used in Example 1 ^ 1156 g, crospovidone (ISP company, Polyplasdon XL-10) 24 g Extruded granulator (Fuji Padal, DGL-) was charged into a stirring granulator (NSK-250, manufactured by Okada Seie), added with 200 g of purified water, kneaded for 5 minutes, and equipped with a 0.8πιπιφ screen. :! Type) to prepare granules After that, it was dried at 60 ° C for 60 minutes using a ventilation box type dryer (Nihon Dryer TE-98). The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Φ 7. Om m Use a rotary tableting machine equipped with a punch with a square flat surface and a device for applying calcium stearate to the punch surface and the die wall before filling the granules into the die of the tableting machine. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 120 mg and a tablet thickness of 2.6 mm. The tableting pressure was about 7.5 kN. About 0.1% by weight of calcium stearate (lubricant) was adhered to the surface of the obtained tablet. (Example 3)

Midodrine hydrochloride (solubility in water about 1 O OmgZml) 20 g, D-mannitol (Kyowa Hakko / Nikken Kasei Co., Ltd., average particle diameter 35 m, specific surface area 0.3 mVg) 1120 g, crospovidone (ISP Polyplasdone XL-1 Oj) 6 Og was charged into a high-speed stirring granulator (NSK-250, manufactured by Okada Seie), purified water 20 Og was added and kneaded for 5 minutes. After preparing granules using an extrusion granulator equipped with an 8ππηφ screen (manufactured by Nonipadal, DGL-1 type), using a ventilation box type drier (Nippon Drier ΤΕ_98 type) for 60 minutes The obtained dried product was sized with a wire gauze No. 20 to obtain granules for tableting.Φ 7. Attach a punch with an Omm corner flat surface, and before filling the granules into a die of a tableting machine, calcium stearate. The obtained granules for tableting were compression-molded using a rotary tableting machine equipped with a device for applying the tablet to the surface of the punch and the mortar wall, and the tablet weight was 120 mg. A tablet with a tablet thickness of 2.6 mm was produced, with a tableting pressure of about 7.5 kN, and about 0.1% by weight of calcium stearate (lubricant) on the surface of the obtained tablet. [Example 4]

Midodrine hydrochloride (water solubility about 100 mgZm 1) 20 g, used in Example 1 1060 g of D-mannitol and 12 Og of crospovidone (ISP, “Polyplusdon XL-10”) were charged into a high-speed stirring granulator (NSK-250, manufactured by Okada Seie), and 200 g of purified water was added. The mixture is kneaded for 5 minutes, and the granulated material is prepared using an extrusion granulator equipped with a 0.8 mmci) screen (manufactured by Fuji Padal, Model DGL-1). (TE-98 machine) at 60 ° C for 60 minutes. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Use a rotary tableting machine equipped with a Φ 7.0 mm corner flat punch and equipped with a device to apply calcium stearate to the punch surface and the die wall before filling the granules into the mill of the tableting machine. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 12 Omg and a tablet thickness of 2.6 mm. The tableting pressure was about 7.5 kN. About 0.1% by weight of calcium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Comparative Example 1)

Domperidone (solubility in water about 2 ^ g / m 1) 200 g and D-mannitol (Kyowa Hakko Niken Kasei Co., Ltd., specific surface area 0.1 lm ² / g, average particle diameter 60 m) 2080 g, crospovidone 120 g was charged into a fluidized bed granulation dryer (FLO-2, manufactured by Freund Corporation), and 50 ml of purified water was sprayed to obtain a granulated product. 1190 g of the obtained granules and 10 g of magnesium stearate were added to obtain granules for tableting. 7 The obtained granules for tableting were compression-molded using an open-ended tableting machine equipped with a φ-plane punch, and the tablet weight was 120 mg and the tablet thickness was 2.55, 2.60 and 2, respectively. 65 mm tablets were produced. The tableting pressure was about 10 kN, about 7.5 kN and about 6 kN, respectively. The resulting tablets contained 0.8% by weight of magnesium stearate (lubricant).

(Comparative Example 2) D-mannitol (manufactured by Kyowa Hakko / Nikken Kasei Co., Ltd., specific surface area: 0.1 lmVg, average particle size: 60 urn) 2260 g and crospovidone 120 g were fluidized-bed granulation dryer (FLO-2 type manufactured by Freund Corporation) , And sprayed with 50 ml of purified water to obtain granules. 1190 g of the obtained granules and 10 g of magnesium stearate were added to obtain granules for tableting. 7 圧縮 Using a rotary type tableting machine equipped with a flat punch, the obtained granules for tableting were compression-molded to a tablet weight of 120 mg and a tablet thickness of 2.55, 2.60 and 2.65, respectively. mm tablets were produced. The tableting pressure was about 10 kN, about 7.5 kN and about 6 kN, respectively. The resulting tablets contained 1.0% by weight of magnesium stearate (lubricant).

(Example 5)

Ambroxol hydrochloride (solubility in water: about 2 OmgZml) 300 g, D-mannitol 1980 g used in Example 1, crospovidone (ISP, "Polyplasdone XL-10") 120 g granulated at high speed The mixture was charged into a machine (VG-25, manufactured by Baurek), purified water was added to the mixture, and the mixture was granulated. The resulting mixture was dried at 80 ° C for 15 minutes using a fluidized-bed drier (FLO-5, manufactured by Freund). The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. A rotary type tableting machine equipped with a punch with a φ7.0 mm square plane and equipped with a device for applying magnesium stearate to the surface of the punch and the wall of the die before filling the granules into the die of the tableting machine The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 12 Omg and tablet thicknesses of 2.55, 2.60 and 2.65 mm, respectively. The tableting pressure was about 10 kN, about 7.5 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Example 6)

Ambroxol hydrochloride (solubility in water about 2 OmgZm 1) 300 g, Example 1980 g of D-mannitol used in 1 and crospovidone (polyplasdone XL-10, manufactured by ISP) and 12 Og were charged into a high-speed stirring granulator (VG-25, manufactured by Palek), and purified water was added. After adding 400 g and granulating, the mixture was dried at 80 ° C for 15 minutes using a fluid bed dryer (FLO-5, manufactured by Freund Industries), and the obtained dried product was sized with a No. 20 wire mesh. 990 g of the granules were mixed with 10 g of magnesium sterate to give granules for tableting. The obtained granules for tableting were compression-molded using a rotary tableting machine equipped with a phi 7.0 mm square flat punch, and the tablet weight was 120 mg and the tablet thickness was 2.55 and 2.60, respectively. And 2.65 mm tablets were produced. The tableting pressure was about 10 kN, about 7.5 kN and about 6 kN, respectively. The resulting tablets contained 1.0% by weight of magnesium stearate (lubricant).

(Example 7)

Ambroxol hydrochloride (solubility in water: about 2 Omg / m 1) 300 g, D-mannitol 1980 g used in Example 1 and crospovidone (ISP, “Polyplasdone XL-10”) 120 g Charge into a high-speed agitation granulator (VG-25, manufactured by Baurek), add 400 g of purified water, granulate, and dry using a fluid bed dryer (FLO-5, manufactured by Freund) for 80） 5 minutes. The obtained dried product was sized with a No. 20 wire mesh. 990 g of the granules were mixed with 9 g of magnesium stearate to prepare granules for tableting. Using a rotary type tableting machine equipped with a punch with a φ7.0 mm corner plane and a device for applying magnesium stearate to the surface of the punch and the die wall before filling the granules into the mill of the tableting machine The obtained granules for tableting were compression molded to produce tablets having a tablet weight of 12 Omg and tablet thicknesses of 2.55, 2.60 and 2.65 mm, respectively. The tableting pressure was about 10 kN, about 7.5 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface of the obtained tablet. Also, in the tablets, stearic acid Gnesium (lubricant) was contained at 0.9% by weight. (Example 8)

15 g of peramide hydrochloride (solubility in water: about lmg / ml), 1410 g of D-mannitol used in Example 1, and 75 g of crospovidone (polyplasdone XL-10, manufactured by ISP) The mixture was charged in a layer granulation dryer (FLO-2, manufactured by Freund Corporation), sprayed with 50 ml of purified water, and granulated and dried. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. A single-tally tableting machine equipped with a device that applies calcium stearate to the surface of the punch and the wall of the mortar before filling the granules into the mortar of the tableting machine was fitted with a punch having a Φ6.5 mm corner flat surface. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 100 mg and a tablet thickness of 2.3 mm. The tableting pressure was about 6 kN. About 0.1% by weight of calcium stearate (lubricant) was adhered to the surface of the obtained tablet. (Comparative Example 3)

Peramide hydrochloride (water solubility approx. Lmg / m 1) 15 g, sorbitol (Towa Kasei Co., Ltd.) 1410 g, Crospovidone (ISP, “Polyplasdone XL-10”) 75 g The mixture was charged in a layer granulation dryer (FLO-2, manufactured by Freund Corporation), and sprayed with 50 ml of purified water to granulate and dry. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Using a rotary tableting machine equipped with a φ6.5 mm corner flat punch and a device that applies calcium stearate to the punch surface and the die wall before filling the granules into the die of the tableting machine The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 100 mg and a tablet thickness of 2.3 mm. The compression pressure was about 6 kN. About 0.1% by weight of calcium stearate (lubricant) was adhered to the surface of the obtained tablet. (Comparative Example 4)

Fluid bed granulated and dried 15 g of peramide hydrochloride (solubility in water: about lmgZml), 1410 g of sucrose (manufactured by Nissin Sugar Co., Ltd.), and 75 g of crospovidone (manufactured by ISP, "Polyplasdone XL-10") It was charged into a machine (FLO-2, manufactured by Freund Corporation), sprayed with 800 g of purified water and granulated and dried. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Using a rotary type tableting machine equipped with a punch with a Φ 6.5 mm corner flat surface and a device for applying calcium stearate to the surface of the punch and the die wall before filling the granules into the mortar of the tableting machine The granules for tableting obtained in this manner were compression-molded to produce tablets having a tablet weight of 100 mg and a tablet thickness of 2.3 mm. The tableting pressure was about 6 kN. About 0.1% by weight of calcium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Example 9)

Captopril (solubility in water about 6 Omg / m 1) 250 g, D-mannitol used in Example 1 (Kyowa Hakko Z Niken Kasei Co., Ltd., specific surface area 0.1 lm ² Zg) 14 60 g, crospovidone ( 90 g of “ISPL,“ Polyplasdone XL-10 ”) is charged into a high-speed agitating granulator (VG-25, manufactured by PALEK), 350 g of purified water is added, and granulation is carried out. It was dried at 80 ° C for 15 minutes using an industrial FLO-5 type. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting.

8. Use a single-tally tableting machine equipped with a punch with a 0 mm corner flat surface and equipped with a device for applying magnesium stearate to the surface of the punch and the wall of the die before filling the granules into the die of the tableting machine. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 180 mg and tablet thicknesses of 2.95, 3.00 and 3.05 mm, respectively. The tableting pressure was about 1 lkN, about 8 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was attached to the surface of the obtained tablet. (Comparative Example 5)

Captopril (solubility in water about 6 OmgZml) 250 g, sorbitol (Towa Kasei Co., Ltd.) 1460 g, Crospovidone (ISP, "Polyplasdone XL-10") 9 Og with high-speed stirring granulator (Model VG-25 manufactured by Pallek Co., Ltd.), and after adding 350 g of purified water to granulate, the mixture was dried at 80 ° C. for 15 minutes using a fluidized-bed dryer (Model FL-5, manufactured by Freund Corporation). The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Single-tally tableting machine equipped with a φ8 Omm corner flat punch and equipped with a device to apply magnesium stearate to the punch surface and the die wall before filling the granules into the die of the tableting machine The tableting pressure was adjusted using to produce tablets having a tablet weight of 180 mg and a tablet thickness of 2.95, 3.00 and 3.05 mm, respectively. The tableting pressure was about 1 lkN, about 8 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Comparative Example 6)

Captopril (solubility in water of about 6 OmgZml) 250 g, white sugar (Nissin Sugar Co., Ltd.) 1460 g, crospovidone (ISP Co., "Polyplasdone XL-10") 9 Og with high-speed stirring granulator (Model VG-25 manufactured by Pallek Co., Ltd.), 35 Og of purified water was added to the mixture, and the mixture was granulated and dried using a fluidized bed drier (Model FLO-5 manufactured by Freund Corporation) for 80 to 15 minutes. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Φ 8. Omm corner type flat punch, equipped with a device that applies magnesium stearate to the punch surface and die wall before filling the granules into the die of the tableting machine. The tableting pressure was adjusted to produce tablets having a tablet weight of 180 mg and a tablet thickness of 2.95, 3.00 and 3.05 mm, respectively. The tableting pressure was about 11 kN, about 8 kN and about 6 kN, respectively. Of the resulting tablet About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface.

(Example 1.0)

Captopril (solubility in water: about 6 Omg / m 1) 250 g, D-manni! ^ 1 (Kyowa Hakko Niken Kasei Co., Ltd., average particle diameter 30 m, specific surface area 0.4 m ² / g) 1460 g, Crospovidone (ISP, "Polyplasdone XL-10") 9 Og is charged into a high-speed agitation granulator (PAREX VG-25), purified water 35 Og is added, and the mixture is fluidized. It was dried at 80Π for 5 minutes using a layer dryer (FLO-5, manufactured by Freund Corporation). The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Use a rotary tableting machine equipped with a punch with an Omm corner flat surface and a device that applies magnesium stearate to the surface of the punch and the die wall before filling the granules into the die of the tableting machine. The obtained granules for tableting were compression-molded to produce disintegrants having a tablet weight of 180 mg and tablet thicknesses of 2.95, 3.00 and 3.05 mm, respectively. The tableting pressure was about 11 kN, about 8 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Comparative Example 7)

Captopril (solubility in water: about 6 Omg / m 1) 250 g, D-mannitol 1460 g used in Example 1, croscarmellose sodium (Asahi Kasei Co., Ltd., “Ac—Di_So 1 J”) 90 g Was charged into a high-speed agitation granulator (VG-25, manufactured by Parek), added with 350 g of purified water, granulated, and dried at 80 ° C for 15 minutes using a fluidized bed drier (FLO-5, manufactured by Freund Corporation). The obtained dried product was sized with a wire mesh to obtain granules for tableting.Φ 8. Omm has a flat punch with a flat corner, and magnesium stearate was added before filling the granules into a die of a tableting machine. Apply to punch surface and die wall The obtained granules for tableting are compression-molded using a rotary type tableting machine equipped with a device to perform tableting, with a tablet weight of 180 mg and a tablet thickness of 2.95, 3.00 and 3.05 mm, respectively. Tablets were produced. The tableting pressure was about 11 kN, about 8 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface of the obtained tablet.

(Comparative Example 8)

Captopril (solubility in water: about 6 Omg / m 1) 250 g, D-manni used in Example 1 1460 g, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd., “L_HPC LH31 j”) 90 g was charged into a high-speed agitation granulator (Model PE-VG VG-25), 350 g of purified water was added, and the mixture was granulated. Using a fluidized-bed dryer (FLO-5 type manufactured by Freund Industries) at 80 ° C The obtained dried product was sized with a wire mesh No. 20 to obtain granules for tableting, which had a punch with a φ8.0 mm corner flat surface and before filling the granules into a mill of a tableting machine. The tableting pressure was adjusted using a single-tally type tableting machine equipped with a device for applying magnesium stearate to the surface of the punch and the die wall, and the tablet weight was 18 Omg and the tablet thickness was 2.95, respectively. Tablets of 3.00 and 3.05 mm were produced, with tableting pressures of about 11 kN, about 8 kN, and about 6 kN, respectively. On the surface, about 0.1 wt% of stearic phosphate magnesium (lubricant) was adhered.

(Comparative Example 9)

Captopril (solubility in water of about 6 OmgZm 1) 250 g, D-manniyl (Kyowa Hakko Z Niken Kasei Co., Ltd., average particle diameter 7 m, specific surface area 1. ImVg) 1 460 g, crospovidone (ISP 90 g of Polyplasdone XL-10) into a high-speed agitating granulator (VG-25, manufactured by Palek), adding 350 g of purified water to granulate, and then using a fluid bed dryer (Freund Sangyo) FLO—type 5) and 8 Dried at 0 ° C for 15 minutes. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. A rotary type 1 tableting machine equipped with a punch with a Φ 8.0 mm corner flat surface and equipped with a device for applying magnesium stearate to the surface of the punch and the die wall before filling the granules into the mill of the tableting machine. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 180 mg and tablet thicknesses of 2.95, 3.00 and 3.05 mm, respectively. The tableting pressure was about 11 kN, about 8 kN and about 6 kN, respectively. About 0.1% by weight of magnesium stearate (lubricant) was attached to the surface of the obtained tablet.

The table below shows the composition of the tablets.

Table 1

In the table, EX indicates that the lubricant was previously applied to the punch and die wall of the tableting machine, and the lubricant was contained on the surface of the tablet by tableting using the tableting machine. The percentages in the table represent% by weight. Table 2

In the table, the active ingredient is a pharmacologically active ingredient, specifically, amproxo hydrochloride.

—Le In the table, EX indicates that the lubricant was previously applied to the punch and the die wall of the tableting machine, and that the lubricant was contained on the surface of the tablet by tableting using the tableting machine. . The percentages in the table represent% by weight. Table 3

In the table, the active ingredient is a pharmacologically active ingredient, specifically, peramide hydrochloride. In the table, EX indicates that the lubricant was previously applied to the punch and die wall of the tableting machine, and the lubricant was contained on the surface of the tablet by tableting using the tableting machine. Table 4

In the table, the active ingredient is a pharmacologically active ingredient, specifically, captopril. EX in the table indicates that the lubricant was previously applied to the punch and the die wall of the tableting machine, and the lubricant was contained on the surface of the tablet by tableting using the tableting machine.

(Test example)

The oral disintegration time and hardness of the tablets of Example 110 and Comparative Example 17 were measured. For the oral disintegration time, one tablet was contained in the oral cavity for five healthy adults, and the time required for the tablet to disintegrate with saliva alone was measured, and the average value was calculated. Also tablet hardness The tablet hardness was measured by using a tablet hardness tester (TH-303, manufactured by Toyama Chemical Co., Ltd.) for each tablet, and the average value was calculated. The following table shows the results.

In Comparative Examples 1 and 2, the tablet hardness did not increase from about 15 N even when a tableting pressure of 10 kN or more was applied. The occurrence of lamination was also confirmed. Table 5

Table 6

Tablet thickness 2.55 Maraud 2.6 thigh 2.65 thigh

Hardness: Disintegration time Hardness: Disintegration time Hardness: Disintegration time Example 5 6 ON, 13s 57N, 13s 43N, 12s

Example 6 39 N, 33 s 36 N, 27 s 2 ON, 21 s

Example 7 41 N, 27 s 39 N, 25 s 15 N, 22 s Table 7

Table 8

(Example 11)

Famotidine (solubility in water: about 0.7 mg / ml) 100 g, D-mannitol (Kyowa Hakko No Nikka Kasei Co., Ltd., average particle diameter 60 im, specific surface area 0.1 lmVg) 1040 g, crospovidone (I 60 g of SPILL, “Polyplasdone XL-10”) was charged into a high-speed stirring granulator (NSK-250, manufactured by Okada Seie), 200 g of purified water was added, and the mixture was kneaded for 5 minutes. After preparing granules using an extrusion granulator equipped with a mm Φ screen (manufactured by Nonpadal, DGL-1 type), a ventilation box type dryer (Nippon Drying Machine TE_98 type), dried at 60 ° C for 60 minutes. The obtained dried product was sized with a No. 20 wire mesh to obtain granules for tableting. Φ7. Using a rotary tableting machine equipped with an Omm corner flat punch, and a device for applying magnesium stearate to the punch surface and the die wall before filling the granules into the die of the tableting machine. The obtained granules for tableting were compression-molded to produce tablets having a tablet weight of 120 mg and a tablet thickness of 2.6 mm. The tableting pressure was about 8 kN. About 0.1% by weight of magnesium stearate (lubricant) was adhered to the surface of the obtained tablet. The hardness of the obtained tablet was 43 N, and the disintegration time in the oral cavity was about 16 seconds. Industrial applicability

INDUSTRIAL APPLICABILITY According to the present invention, a rapidly disintegrating intraoral tablet having a practical tablet hardness that disintegrates quickly without water in the oral cavity, and does not cause problems such as shape loss in the manufacturing and distribution processes and in the process of handling by hospitals and patients. Can be provided. Such a rapidly disintegrating intraoral tablet can easily take the correct amount of drug even in patients with weak swallowing, such as elderly people and children, and can be used without water in ordinary patients, even when going out where water is not available. Since it can be taken, it has the advantage of improving drug compliance for all patients.

Claims

Range of request

1. Pharmacologically active ingredients with a solubility in water of 0.5 mg Zml or more, D-mannitol crystals or fine particles with an average primary particle diameter of 30 / m or more and a specific surface area of 0.4 m ² Zg or less, and A rapidly disintegrating oral tablet containing crospovidone.

2. Contains midodrine or its pharmacologically acceptable salt, D-mannitol crystals or fine particles with an average primary particle size of 30 m or more and a specific surface area of 0.4 m ² Zg or less, and crospovidone Oral fast-disintegrating tablet.

3. The tablet according to claim 2, wherein the midodrine or a pharmaceutically acceptable salt thereof is midodrine hydrochloride.

4. The tablet according to any one of claims 1 to 3, further comprising a lubricant.

5. The tablet according to claim 4, wherein the lubricant is contained only on the surface of the tablet.

6. The lubricant according to claim 4, wherein the lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, sodium stearyl fumarate, sucrose fatty acid ester and talc. The tablet according to any one of the above items 5.

7. Claims 1 to 6 further comprising at least one selected from the group consisting of flavoring agents, sweeteners, flavors and coloring agents, stabilizers, antioxidants, glidants, and solubilizers. The tablet according to any of the above items.

8. The tablet according to any one of claims 1 to 7, wherein the compounding ratio of the pharmacologically active ingredient in the tablet is 0.01 to 50% by weight.

9. The tablet according to any one of claims 1 to 8, wherein the content of D-mannitol in the tablet is 20 to 99% by weight.

10. The tablet according to any one of claims 1 to 9, wherein the compounding ratio of crospovidone in the tablet is 0.5 to 30% by weight.

11. The tablet according to any one of claims 1 to 10, wherein the tablet hardness is 2 ON or more.

12. The tablet according to any one of claims 1 to 11, wherein the disintegration time in the oral cavity is 30 seconds or less.

13. The tablet according to any one of claims 1 or 4 to 12, wherein the pharmacologically active ingredient is midodrine hydrochloride.

14. Pharmacologically active ingredients with a solubility in water of 0.5 mg Zm 1 or more, crystals or fine particles of D-mannitol having an average primary particle size of 30 xrn or more and a specific surface area of 0.4 m ² Zg or less, and An aqueous medium is added to the granules containing crospovidone, and the mixture is kneaded, and then granulated, and then, if necessary, other additives are added to the granules obtained by drying to prepare a compression molding material. A method for producing an orally rapidly disintegrating tablet, characterized by compression molding.

15. Midodrine or pharmacologically acceptable salt thereof, average primary particle size Is not less than 30 m and the specific surface area is not more than 0.4 m ² / g. D-manni! A mixture obtained by adding an aqueous medium to granules containing crystals or fine particles and crospovidone A process for producing a rapidly disintegrating tablet in the oral cavity, characterized by preparing a compression-molded material by adding other additives to the granules obtained by granulating and then drying, if desired, and compression-molding the material.

16. The method for producing a tablet according to claim 15, wherein the midodrine or a pharmaceutically acceptable salt thereof is midodrine hydrochloride.

17. The claim wherein the other additive comprises at least one selected from the group consisting of a flavoring agent, a sweetening agent, a flavor and a coloring agent, a superplasticizer, an antioxidant, a stabilizer, and a solubilizing agent. 17. The method for producing a tablet according to any one of items 14 to 16.

18. The method for producing a tablet according to any one of claims 14 to 17, wherein the powder further comprises a lubricant.

19. The method according to any one of claims 14 to 18, wherein the compression molding is performed using a compression molding machine in which a lubricant is applied to the surface of the punch and the wall of the mortar in advance. Manufacturing method of the above-mentioned tablet.

20. The lubricant is at least one selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, sodium stearyl fumarate, sucrose fatty acid ester and talc. 10. The method for producing a tablet according to any one of items 18 and 19.

21. The claim wherein the compounding ratio of the pharmacologically active ingredient in the tablet is 0.01 to 50% by weight. 20. The method for producing a tablet according to any one of items 14 to 20.

22. The method for producing a tablet according to any one of claims 14 to 21, wherein the compounding ratio of D-mannitol in the tablet is from 20 to 99% by weight.

23. The method for producing a tablet according to any one of claims 14 to 22, wherein the compounding ratio of crospovidone in the tablet is 0.5 to 30% by weight.

24. The method for producing a tablet according to any one of claims 14 to 23, wherein the tablet hardness of the obtained spear is 2 ON or more.

25. The method for producing a tablet according to any one of claims 14 to 24, wherein the disintegration time of the obtained tablet in the oral cavity is 30 seconds or less.

26. The method for producing a tablet according to any one of claims 14 to 25, wherein the aqueous medium is pure water.

27. The method for producing a tablet according to any one of claims 14 or 17 to 26, wherein the pharmacologically active ingredient is midodrine hydrochloride.

28. A pharmacologically active ingredient with a solubility in water of 1 mg Zm 1 or more, a crystal of D-mannitol or a primary particle having an average particle diameter of 30 m or more and a specific surface area of 0.4 m ² Zg or less. A rapidly disintegrating oral tablet containing microparticles and crospovidone.